Recent observations by the applicants suggest that adoptive transfer of T cells genetically modified to express a B cell-specific antibody, incorporated into an artificial chimeric T-cell receptor (CAR), might eradicate lymphoma cells in a clinical setting. The intent of this proposal is to test whether transgenic T cells that express CAR targeted to the kappa-light chain of immunoglobulin can be safely administered to patients with follicular lymphoma and whether such immunotherapy induces antitumor effects without impairing humoral immunity. This objective will be vigorously pursued in three specific research aims. First, it will be important to validate and maximize the function of CAR-bearing T cells both in vitro and. in a SCID mouse model and to devise optimal assaysfor evaluating the persistence and functionality of the transgenic T cells after their infusion into lymphoma patients. Second, the clinical significance of the laboratory findings underlying this project will be tested in a Phase I trial designed to evaluatethe safety, properties and antitumor activity of the modified T cells in patients with refractory/relapsed lymphoma, using the biological assays developedin Aim 1to assessT-cell function and persistence. Third, studies are planned to extend the value of the CAR-expressing T cells by engineering them to produce a CD22-targeted immunotoxin after the anti-CD19 CAR is engaged by antigen. If safe and effective in a murine xenograft model, this combined strategy of adoptive T cell immunotherapy, which exploits two distinct classes of effector mechanisms, will undergo testing in future clinical trials not funded by this award. Upon completion of these aims, it should be clear whether the infusion of anti-kappa CAR-expressingT cells is a legitimate approach to the treatment of human follicular lymphoma, and whether the inducible release of immunotoxin by these cells at the tumor site will enhance antitumor activity. Lay Abstract: Follicular lymphoma cannot be cured by chemotherapy.Since these tumor cells can occasionally be recognized and eliminated by other cells of the immune system (T lymphocytes) we will genetically alter these T lymphocytesinserting an artificial receptor that recognizes a structure on the surface of the cancerous B cells. When the T lymphocytes contact the tumor cells, they become activated and kill the cancer. This effect should not significantly damage the remaining normal B-cells preserving the immunity.